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Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices.

Min-Yu Sun1, Yukitoshi Izumi2, Ann Benz1

  • 1Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri;

Journal of Neurophysiology
|January 9, 2016
PubMed
Summary

Reduced brain cholesterol metabolite 24S-hydroxycholesterol (24S-HC) lowers N-methyl-D-aspartate receptor (NMDAR) activity. Loss of NMDAR tone protects against oxygen-glucose deprivation-induced synaptic dysfunction, offering therapeutic potential for neurological disorders.

Keywords:
24S-hydroxycholesterolCYP46A1 knockout miceNMDARhippocampal slice

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • N-methyl-D-aspartate receptors (NMDARs) are crucial for central nervous system (CNS) function and cognition.
  • NMDAR dysfunction is implicated in neurological and psychiatric disorders like stroke and schizophrenia.
  • The cholesterol metabolite 24S-hydroxycholesterol (24S-HC) is known to positively modulate NMDARs.

Purpose of the Study:

  • To investigate whether endogenous 24S-hydroxycholesterol (24S-HC) regulates NMDAR activity in hippocampal slices.
  • To determine the functional consequences of reduced endogenous 24S-HC on synaptic transmission and neuronal excitability.
  • To assess the role of 24S-HC in protecting against NMDAR-mediated synaptic dysfunction.

Main Methods:

  • Electrophysiological recordings in hippocampal slices from wild-type (WT) and CYP46A1 knockout (KO) mice, which have reduced endogenous 24S-HC.
  • Measurement of NMDAR and AMPAR excitatory postsynaptic current (EPSC) ratios.
  • Assessment of spontaneous neurotransmission, intrinsic neuronal excitability, and long-term potentiation (LTP).
  • Induction of oxygen-glucose deprivation (OGD) to model ischemic conditions and assess synaptic transmission resilience.

Main Results:

  • CYP46A1 KO slices exhibited reduced NMDAR tone compared to WT slices.
  • No significant differences were observed in spontaneous neurotransmission, intrinsic excitability, or LTP between WT and KO slices.
  • KO slices showed enhanced resistance to OGD-induced synaptic depression, an effect reversed by the 24S-HC analog SGE-301.
  • SGE-301 demonstrated potentiating effects on NMDAR EPSCs in both WT and KO slices, indicating non-saturating modulation by endogenous 24S-HC.

Conclusions:

  • Endogenous 24S-hydroxycholesterol positively modulates NMDAR activity in the hippocampus.
  • Reduced NMDAR tone due to lower 24S-HC levels does not alter baseline synaptic function or excitability.
  • Loss of NMDAR tone confers protection against NMDAR-mediated synaptic dysfunction during ischemic conditions.
  • Targeting the 24S-HC pathway presents a potential therapeutic strategy for neuropsychiatric disorders associated with NMDAR dysfunction.